Process for the preparation of aryloctanoyl amides

ABSTRACT

Compounds of formula I  
                 
 
     wherein  
     R 1  is for example 3-methoxyprop-3-yloxy, R 2  is for example methoxy, R 3  and R 4  are in each case for example isopropyl, and R 5  is H 2 NC(O)—[C(CH 3 ) 2 ]—CH 2 —, are obtainable by reaction of compounds of formula IV  
                 
 
     with a metal organic derivative of 1-(3-R 1 -4-R 2 -phen-1-yl)-2-R 3 -3-halogen propanes to form a compound of formula VI,  
                 
 
     followed by removal of the pseudoephedrine protecting group and the OH group, reaction of the resulting lactone with an amine R 5 —NH 2  and removal of protecting group Z.

[0001] The invention relates to a stereospecific method for thepreparation of2(S),4(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amides inthe form of 5(R)- or 5(S)-diastereomers and mixtures thereof, as well astheir physiologically acceptable salts; and new compounds used in themultistage process as intermediates.

[0002] In EP-A-0 678 503, δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamidesare described, which exhibit renin-inhibiting properties and could beused as antihypertensive agents in pharmaceutical preparations. Themanufacturing procedures described are unsatisfactory in terms of thenumber of process steps and yields and are not suitable for anindustrial process. A disadvantage of these processes is also that thetotal yields of pure diastereomers that are obtainable are too small.

[0003] D. A. Sandham et al. describe in Tetrahedron Letters, Volume 41,Issue 51, pages 10085-10089 (2000), a synthesis for the preparation of2(S),4(S),5(S),7(S)-2-isopropyl-4-hydroxy-5-amino-7-isopropyl-8-[(3-methoxy-n-propoxy)-4-methoxyphenyl]octanoylamide, in which a Grignard compound of1-[(3-methoxy-n-propoxy)-4-methoxyphenyl]-2-isopropyl-3-chloropropane isreacted with a pseudoephedrine-protected isopropylvalerolactonealdehyde, followed by hydrolysis, to form a compound of formula A

[0004] The compound of formula A is obtained in a yield of only 51%, theR:S ratio, in relation to the OH group, being 85:15. The OH group isthen converted to a leaving group (brosylate). The reaction with sodumazide yields the corresponding azido compound which with3-amino-2,2-dimethylpropionamide on opening of the lactone ring givesthe corresponding amide. Catalytic hydrogenation then yields the desiredamine.

[0005] It has now been surprisingly found that these alkanecarboxamidesare obtainable both in high total yields and in a high degree of puritywhen the amino group is introduced with Grignard coupling. According tothis process step, customary purification and separation procedures canif necessary be used for the preparation of pure diastereomers. Theprocess is suitable for industrial scale manufacture.

[0006] A first object of the invention is a process for the preparationof compounds of formula I and their physiologically acceptable salts,

[0007] wherein

[0008] R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₅ isC₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆-alkyl,C₁-C₆alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl,C₁-C₆alkylamino-C₁-C₆-alkyl, C₁-C₆-dialkylamino-C₁-C₆-alkyl,C₁-C₆-alkanoylamido-C₁-C₆-alkyl, HO(O)C—C₁-C₆-alkyl,C₁-C₆alkyl-O—(O)C—C₁-C₆alkyl, H₂N—C(O)—C₁-C₆alkyl,C₁-C₆alkyl-HN—C(O)—C₁-C₆alkyl or (C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl,comprising the steps

[0009] a) reaction of a compound of formula II,

[0010] wherein R₄ is as defined above, with a hydroxylamine of formulaZNHOH (III), wherein Z is a removable protecting group, to form acompound of formula IV,

[0011] b) reaction of a compound of formula IV with a metal organicderivative of a compound of formula V,

[0012] wherein R₁, R₂ and R₃ are as defined above, and Y is Cl, Br or I,to form a compound of formula VI,

[0013] c) removal of the hydroxyl group to form a compound of formulaVII,

[0014] d) removal of the pseudoephedrine protecting group to formcompounds of formula VIII,

[0015] or the performance of step d) before step c), or the performanceof steps c) and d) together in one reaction vessel,

[0016] e) reaction of a compound of formula VIII with an amine offormula R₅—NH₂ to form a compound of formula IX

[0017] and

[0018] f) removal of protecting group Z for the preparation of compoundsof formula I.

[0019] With the process according to the invention, preferably the5(S)-diastereomer of formula Ia

[0020] is prepared.

[0021] As an alkyl, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl,n-, i- and t-butyl, pentyl and hexyl.

[0022] As a halogenalkyl, R₁ and R₂ may be linear or branched andpreferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examplesare fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

[0023] As an alkoxy, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- andi-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

[0024] As an alkoxyalkyl, R₁ and R₂ may be linear or branched. Thealkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms,and the alkyl group preferably comprises 1 to 4 C atoms. Examples aremethoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl,methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl,1-ethoxy-prop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl,propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and1-butyloxyeth-2-yl.

[0025] As a C₁-C₆alkoxy-C₁-C₆alkyloxy, R₁ and R₂ may be linear orbranched. The alkoxy group preferably comprises 1 to 4 and especially 1or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 Catoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy,1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy,methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy,1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy,ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy,1-propyloxyeth-2-yloxy and 1-butyl-oxyeth-2-yloxy.

[0026] In a preferred embodiment, R₁ is methoxy- orethoxy-C₁-C₄alkyloxy, and R₂ is preferably methoxy or ethoxy.Particularly preferred are compounds of formula I, wherein R₁ is1-methoxyprop-3-yloxy and R₂ is methoxy.

[0027] As an alkyl, R₃ and R₄ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl,n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R₃ andR₄ in compounds of formula I are in each case isopropyl.

[0028] As an alkyl, R₅ may be linear or branched and preferably comprise1 to 4 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl,n- and i-propyl, n-, i- and t-butyl are preferred.

[0029] As a C₁-C₆hydroxyalkyl, R₅ may be linear or branched andpreferably comprise 2 to 6 C atoms. Some examples are2-hydroxyethy-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.

[0030] As a C₁-C₆alkoxy-C₁-C₆alkyl, R₅ may be linear or branched. Thealkoxy group preferably comprises 1 to 4 C atoms and the alkyl grouppreferably 2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl,2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl,2-ethoxyethy-1-yl, 2-ethoxyprop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or4-ethoxybut-1-yl.

[0031] As a C₁-C₆alkanoyloxy-C₁-C₆alkyl, R₅ may be linear or branched.The alkanoyl group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 2 to 4 C atoms. Some examples are formyloxymethyl,formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

[0032] As a C₁-C₆aminoalkyl, R₅ may be linear or branched and preferablycomprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.

[0033] As a C₁-C₆alkylamino-C₁-C₆alkyl andC₁-C₆dialkylamino-C₁-C₆-alkyl, R₅ may be linear or branched. Thealkylamino group preferably comprises C₁-C₄alkyl groups and the alkylgroup preferably 2 to 4 C atoms. Some examples are2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl, 2-ethylaminoeth-1-yl,2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl, 3-dimethylaminoprop-1-yl,4-methylaminobut-1-yl and 4-dimethylaminobut-1-yl.

[0034] As a C₁-C₆alkanoylamido-C₁-C₆alkyl, R₅ may be linear or branched.The alkanoyl group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl,2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and4-butyroylamidoeth-1-yl.

[0035] As a HO(O)C—C₁-C₆alkyl, R₅ may be linear or branched, and thealkyl group preferably comprises 2 to 4 C atoms. Some examples arecarboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

[0036] As a C₁-C₆-alkyl-O—(O)C—C₁-C₆alkyl, R₅ may be linear or branched,and the alkyl groups preferably comprise independently of one another 1to 4 C atoms. Some examples are methoxycarbonylmethyl,2-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl,4-methoxycarbonylbut-1-yl, ethoxycarbonylmethyl,2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonylprop-1-yl, and4-ethoxycarbonylbut-1-yl.

[0037] As a H₂N—C(O)—C₁-C₆alkyl, R₅ may be linear or branched, and thealkyl group preferably comprises 2 to 6 C atoms. Some examples arecarbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl,2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1-yl,3-carbamido-2-methylprop-1-yl, 3-carbamido-1,2-dimethylprop-1-yl,3-carbamido-3-methylprop-1-yl, 3-carbamido-2,2-dimethylprop-1-yl, 2-,3-, 4- or 5-carbamidopent-1-yl, 4-carbamido-3,3- or-2,2-dimethylbut-1-yl.

[0038] As a C₁-C₆alkyl-HN—C(O)—C₁-C₆-alkyl or(C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl, R₅ may be linear or branched, and theNH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl grouppreferably 2 to 6 C atoms. Examples are the carbamidoalkyl groupsdefined hereinabove, whose N atom is substituted with one or two methyl,ethyl, propyl or butyl.

[0039] A preferred subgroup of compounds of formula I is that in whichR₁ is C₁-C₄alkoxy or C₁-C₄alkoxy-C₁-C₄alkyloxy, R₂ is C₁-C₄alkoxy, R₃ isC₁-C₄alkyl, R₄ is C₁-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl which ifnecessary is N-monosubstituted or N-di-C₁-C₄alkyl substituted.

[0040] A more preferred subgroup of compounds of formula I is that inwhich R₁ is methoxy-C₂-C₄-alkyloxy, R₂ is methoxy or ethoxy, R₃ isC₂-C₄alkyl, R₄ is C₂-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl.

[0041] An especially preferred compound of formula I is that in which R₁is 3-methoxy-prop-3-yloxy, R₂ is methoxy, R₃ and R₄ are1-methyleth-1-yl, and R₅ is H₂NC(O)—[C(CH₃)₂]—CH₂—.

[0042] Protecting groups Z in compounds of formula III are generallyknown. Preferred groups are those which can be removed by hydrogenation,such as silyl groups and preferably mono-, di- or triarylmethyl, specialpreference being for mono-, di- or triphenylmethyl. The aryl groups maybe unsubstituted or substituted for example with halogen, C₁-C₄alkyl,C₁-C₄alkoxy or C₁-C₄halogenalkyl. Some examples are naphthylmethyl,methyl- or dimethylbenzyl, methoxy- or dimethoxybenzyl, chlorobenzyl,trifluoromethylbenzyl, benzyl, diphenylmethyl, di(methylphenyl)methyl,di(methoxyphenyl)methyl, trityl, tri(methylphenyl)methyl, tri(methoxyphenyl)methyl, trimethylsilyl, triphenylsilyl andmethyldiphenylsilyl. Benzyl is especially preferred.

[0043] The individual process steps may be carried out in the presenceof solvent. Suitable solvents are water and organic solvents, especiallypolar organic solvents, which can also be used as mixtures of at leasttwo solvents. Examples of solvents are hydrocarbons (petroleum ether,pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene,xylene), halogenated hydrocarbon (methylene chloride, chloroform,tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether,tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether);carbonic ester and lactone (methyl acetate, ethyl acetate, methylpropionate, valerolactone); N,N-substituted carboxamides and lactams(dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones(acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones(dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols(methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol,hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethylcyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol,propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether,and diethylene glycol monomethyl or monoethyl ether; nitriles(acetonitrile, propionitrile); tertiary amines (trimethyl-, triethyl-,tripropyl- and tributylamine, pyridine, N-methylpyrrolidine,N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid,formic acid)

[0044] Process Step a)

[0045] Compounds of formula II are known, and their preparation isdescribed by D. A. Sandham et al. in Tetrahedron Letters, Volume 41,Issue 51, pages 10090ff (2000) . The compounds of formula II areunstable. It is therefore recommended that the aldehyde be preparedimmediately before the reaction with a hydroxylamine. To this end, thecorresponding alcohol is oxidized to the aldehyde for example with acomplex of pyridine and sulfur trioxide, and the aldehyde then extractedfrom the reaction mixture. Before further use, the solvent may bepartially removed for concentration.

[0046] The reaction with a compound of formula III may be carried out attemperatures of −20 to 100° C. and preferably at 0 to 50° C. Thereaction is expediently carried out in an organic solvent, preferably inhalogenated hydrocarbons, for example methylene chloride, chloroform,1,2-dichloroethane or tetrachloroethane. To bind the reaction water, itis advantageous to add a water-binding agent, for example anhydrousmetal salts, such as sodium sulfate or calcium chloride, or silica gels.The hydroxylamine is added in at least equimolar quantities or in slightexcess. The isolation may be carried out in a known manner, for exampleby evaporation of the solvent, filtration of the residue andcrystallization or chromatographic separation of the filtrate. Thecompounds of formula IV are formed in high yields of up to 90% or more.

[0047] Process Step b)

[0048] Metal organic derivatives of a compound of formula V are forexample those of formula X,

[0049] wherein Y₁ is an alkali metal (lithium, sodium and potassium) or—MeY, wherein Y is Cl, Br or iodine and Me is Mg, Zn, Hg or Cd.Preferred compounds are those wherein Y₁ is MgY. The preparation ofmetal organic derivatives from compounds of formula V is known anddescribed in more detail in the example. The reaction is preferablycarried out in ethers or aromatic hydrocarbons as solvents. Someexamples are diethylether, dipropylether, dibutylether,methylpropylether, methylbutylether, tetrahydrofuran and dioxane, aswell as benzene, toluene and xylene. The reaction temperature may be −70to 100 and preferably −30 to 50° C. The compounds of formula IV and themetal organic derivatives of compounds of formula V can be used inequimolar quantities, or an excess of the compounds of said metalorganic derivatives are used. One may proceed in such a way that firstthe said metal organic derivatives are prepared and these added withoutisolation to a solution of a compound of formula IV. The ratio of5(S):5(R)-diastereomer is about 30:70. This ratio may be reversed andessentially increased for example to 70:30 or higher if the reaction iscarried out in the presence of heavy metal salts, or if the said metalorganic derivatives are transmetallated with heavy metal salts (see D.A. Sandham et al. in Tetrahedron Letters, Volume 41, Issue 51, pages10090ff (2000)). Suitable metal salts are those from the group oflanthanides and the first and eighth subgroup of the periodic system ofelements, for example Cu, Fe, Ni and preferably Ce. Especially suitableare the chlorides or sulfates of these metals. The compounds of formulaVI may be isolated in the customary manner by extraction and removal ofthe solvent. Purification may be performed by distillation orchromatography. The pure 5(S)-diastereomer may be obtained by saltformation with chiral acids; or acylation with chiral acid derivativesand recrystallization or chromatography; or directly by chromatographyon chiral columns. The yield may be as high as 80% or more.

[0050] Process Step c)

[0051] The removal of the hydroxyl group is expediently carried out bymeans of reduction, preferably in an aqueous-acidic medium. As reductionagent, hydrogen is preferred. This may be advantageously generated asnascent hydrogen by the addition of metals such as zinc or iron to theaqueous-acidic medium. Suitable acids are organic or inorganic acids,such as acetic acid, hydrochloric acid or sulfuric acid. The presence ofheavy metal salts such as copper diacetate may be advantageous. Thereaction temperature may be 0 to 80° C.

[0052] Process Step d)

[0053] The removal of the pseudoephidrine protecting group may becarried out in aqueous-acidic medium. Suitable acids are organic orinorganic acids, such as acetic acid, hydrochloric acid or sulfuricacid. The reaction temperature may be 0 to 80° C.

[0054] In the context of the invention, process step d) may be carriedout before process step c). It has proved advantageous to carry outprocess steps c) and d) at the same time in one reaction vessel. To thisend, a copper salt and zinc powder may for example be placed in anaqueous acid such as acetic acid, followed by the addition of a solutionof a compound of formula VI in aqueous acid. In this way, a compound offormula VIII is obtainable directly from a compound of formula VI. Thecompound of formula VIII may be isolated by extraction. Purification maythen be carried out by distillation or chromatography. The compound offormula VIII is obtained with a yield of more than 40% using thenon-optimized process.

[0055] Process Step e)

[0056] The reaction of compounds of formula VIII with a compound R₅NH₂on opening of the lactone ring to form compounds of formula IX isexpediently carried out in the presence of alcohols or amines which arecapable of forming activated carbonic esters or carboxamides. Suchcompounds are well-known. They may be 2-hydroxypyridine,N-hydroxycarboxamides and imides, and carboximides(N-hydroxysuccinimide). The solvents used are organic solvents, tertiaryamines being of advantage, for example trimethylamine or triethylamine.The reaction temperature may range for example from approximately 40° C.to 150° C. and preferably from 50° C. to 120° C.

[0057] Process Step f)

[0058] The removal of protecting group Z is expediently carried outcatalytically by hydrogenation in the presence of homogeneous orheterogeneous precious metal catalysts or Raney-Nickel. Homogeneousprecious metal catalysts (Wilkinson catalysts) are soluble metalcomplexes of, for example, platinum, palladium, iridium, rhodium andruthenium, which are known and have been described in the literature.Heterogeneous precious metal catalysts may for example be selected fromthe metals platinum, palladium, iridium, rhodium and ruthenium on, ifnecessary, solid carrier materials such as carbon, metal oxides or salts(aluminium oxide), quartz or silica gels. Organic solvents such asalcohols (methanol, ethanol) may advantageously be used as solvents. Thereaction temperature may range for example from approximately 0° C. to200° C. and preferably from 10° C. to 100° C. Hydrogenation may becarried out at normal pressure or increased pressure up to 100 bar, forexample, and preferably up to 50 bar. It is further expedient to carryout the reaction in the presence of an organic amine (such asethanolamine) in up to equimolar quantities or in slight excess. Theyields are high and may be as much as 90% or more.

[0059] The compounds of formula I may be converted to addition salts ina manner known per se by treatment with monobasic or polybasic,inorganic or organic acids. Hemifumarates are preferred.

[0060] Also an object of the invention are compounds of formula IV,

[0061] wherein R₄ and Z are as defined above, including the preferences.

[0062] A further object of the invention are compounds of formula XI inthe form of 5(S)- or 5(R)-diastereomers or mixtures thereof,

[0063] wherein R₁, R₂, R₃, R₄ and Z are as defined above, including thepreferences, and X₂ is H or OH.

[0064] A further object of the invention are compounds of formula XII inthe form of 5(S)- or 5(R)-diastereomers or mixtures thereof,

[0065] wherein R₁, R₂, R₃, R₄ and Z are as defined above, including thepreferences, and X₂ is H or OH.

[0066] A further object of the invention are compounds of formula XIIIin the form of 5(S)- or 5(R)-diastereomers or mixtures thereof,

[0067] wherein R₁, R₂, R₃, R₄, R₅ and Z are as defined above, includingthe preferences.

[0068] With the choice of compounds of formula IV, the compounds offormula I, which per se are complex compounds, can be prepared in aconvergent and simple manner, which is especially true of thisenantioselective or diastereoselective synthesis. The total yield fromall process steps may amount to 40% or more, which makes an industrialapplication feasible.

[0069] The following examples explain the invention in more detail.

[0070] A) Preparation of

[0071] EXAMPLE A1

[0072] A solution of 0.31 g (2 mmol) pyridine/sulfur trioxide complexand 2 mmol triethylamine in 3 ml dimethyl sulfoxide and methylenechloride (2:1) is added drop by drop over a period of 15 minutes to asolution of 0.2 g (0.65 mmol) compound 1 in 2 ml dimethyl sulfoxide andmethylene chloride (2:1) cooled to 0° C. The reaction mixture is thenheated to ambient temperature and stirred for one hour. The reactionmixture is then poured into 15 ml water while stirring.

[0073] Extraction is carried out with 5×10 ml methylene chloride, thecombined organic phases are washed with concentrated saline solution andthen dried over sodium sulfate. After filtration, the volume isevaporated to 3 ml. This solution of A1 is used directly in the nextreaction.

EXAMPLE B1

[0074] Preparation of

[0075] To 3 ml of the solution described in example A1, 1.44 g anhydroussodium sulfate is added at ambient temperature, followed by 0.089 g(0.72 mmol) benzylhydroxylamine. The mixture is then stirred for 2 hoursat ambient temperature. Filtration is then carried out, followed byevaporation of the solvent and chromatography over silica gel withcyclohexane/acetone (3:2) containing one volume percent oftriethylamine. Compound B1 is obtained in a yield of 88% as a viscousyellow oil. After purification by flash chromatography[cyclohexane/acetone (3:2), 0.5 vol. % triethylamine) the compoundcrystallizes, and after recrystallization in cyclohexane B1 is obtainedas white crystals with a melting point of 75° C.

[0076] Characterization: Melting point: 75-76° C.; [α]_(D) ²⁰=+27.4(c=0.8, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): δ 7.47-7.30 (10 H, m), 6.86 (1H, d, J=4.8 Hz), 5.24 (1 H, m), 4.92 (2 H, s), 4.49 (1 H, d, J=8.6 Hz),2.85 (1 H, dq, J=6.4, 8.6 Hz), 2.35 (1 H, ddd, J=9.6, 12.2, 12.4 Hz),2.28 (3 H, s), 2.17 (1 H, ddd, 3.8, 8.4, 12.2 Hz), 1.86 (1 H, dqq,J=3.8, 6.0, 6.2 Hz), 1.73 (1 H, dt, J=8.4, 12.4 Hz), 1.13 (3 H, d, J=6.0Hz), 1.05 (3 H, d, J=6.2 Hz), 0.92 (3 H, d, J=6.4 Hz). ¹³C-NMR (75 MHz,CDCl₃): δ 141.91 (C═N), 140.20 (NCO₂), 132.40 (aromatic), 129.21 (2 C,aromatic), 128.81 (2 C, aromatic), 128.21 (2 C, aromatic), 127.74 (2 C,aromatic), 126.77 (2 C, aromatic), 122.17 (aromatic), 86.18 (OCH), 69.67(OCH), 68.88 (NCH₂), 65.30 (NCH), 45.95 (NCH₃), 33.12 (CH₂), 30.84 (CH),28.50 (CH), 22.12 (CH₃), 21.10 (CH₃), 15.43 (CH₃).

[0077] C) Preparation of

[0078] from B1

[0079] and

EXAMPLE C1

[0080] Half of a solution of 1.54 g (4.9 mmol) compound Z1 and 20 μl1,2-dibromethane in 10 ml tetrahydrofuran is added drop by drop to asuspension of 0.18 g (7.3 mmol) magnesium powder in tetrahydrofurancontaining a few crystals of iodine and heated to 75° C. After theyellow iodine colour has faded, the other half is added dropwise over 15minutes and then stirred for another 2 hours at 75° C. After cooling toambient temperature, the reaction mixture is added drop by drop over 15minutes to a solution of 0.96 g (2.4 mmol) compound D2 in 6 mltetrahydrofuran which has been cooled to −10° C. The mixture is thenstirred for 15 hours at −10° C. and 40 ml saturated aqueous ammoniumchloride solution added. Extraction is carried out with 4×20 ml ethylacetate, followed by drying over anhydrous sodium sulfate. The solventis evaporated and the residue purified by flash chromatography (mobilephase cyclohexane/acetone 9:1, containing 0.5 vol. % triethylamine).Compound C1 is obtained in a yield of 77% as a colourless oil. The ratioof 5(S)- to 5(R)-stereoisomer is 30:70. The stereoisomers are separatedby chromatography using Jobin Yvon Chromatospac at 6 atmospherespressure (mobile phase cyclohexane/acetone 9:1, containing 0.5 vol. %triethylamine).

[0081] Characterization: Main diastereoisomer: [α]_(D) ²⁰=+54.1 (c=1.0in CHCl₃)H-NMR (300 MHz, CDCl₃): δ 7.48-7.23 (10 H, m), 6.77-6.75 (3 H,m), 4.99 (1 H, bs), 4.59 (1 H, dt, J=4.1, 6.8 Hz), 4.50 (1 H, d, J=8.8Hz), 4.08 (1 H, dt, J=6.4, 9.5 Hz), 4.00 (1 H, dt, J=6.6, 9.5 Hz), 3.82(3 H, s), 3.80 (1 H, d, J=13.7 Hz), 3.72 (1 H, d, J=13.7 Hz), 3.54 (2 H,t, J=6.2 Hz), 3.33 (3 H, s), 2.94 (1 H, dt, J=4.1, 8.0 Hz), 2.86 (1 H,dq, J=6.1, 8.8 Hz), 2.70 (1 H, dd, J=5.4, 13.7 Hz), 2.34 (1 H, dd,J=9.0, 13.7 Hz), 2.26 (3 H, s), 2.07 (2 H, ddt, J=6.2, 6.4, 6.6 Hz),2.05-1.43 (8 H, m), 1.12 (3 H, d, J=5.8 Hz), 1.08 (3 H, d, J=5.1 Hz),1.06 (3 H, d, J=6.6 Hz), 0.96 (3 H, d, J=6.1 Hz), 0.92 (3 H, d, J=6.6Hz). ¹³C-NMR (75 MHz, CDCl₃): δ 148.53 (arom), 147.72 (arom.), 141.20(NCO₂), 139.32 (aromatic), 135.02 (aromatic), 129.36 (2 C, aromatic),128.59 (2 C, aromatic), 128.43 (2 C, aromatic), 128.09 (aromatic),127.41 (2 C, aromatic), 127.22 (aromatic), 121.93 (aromatic), 121.64(aromatic), 114.54 (arom.), 111.91 (aromatic), 86.61 (OCH), 72.92 (OCH),69.66 (OCH₂), 67.84 (OCH₃), 66.21 (OCH₂), 66.03 (OCH3), 59.50 (NCH₂),58.88 (NCH), 56.32 (NCH), 46.23 (CH), 42.90 (NCH₃), 36.20 (CH₂), 32.85(CH₂), 31.72 (CH), 29.86 (CH₂), 29.47 (CH), 28.11 (CH), 26.39 (CH₂),22.72 (CH₃), 21.62 (CH₃), 20.02 (CH₃), 17.75 (CH₃), 15.84 (CH₃).MALDI-TOF MS: 690.5 (M+H).

[0082] Secondary diastereoisomer: ¹H-NMR (300 MHz, CDCl₃): δ 7.52-7.26(10 H, m), 6.86-6.72 (3 H, m), 5.58 (1 H, bs), 4.54 (1 H, d, J=8.4 Hz),4.48 (1 H, m), 4.28 (1 H, d, J=12.9 Hz), 4.09 (1 H, t, J=6.3 Hz), 3.99(1 H, d, J=12.9 Hz), 3.86 (3 H, s), 3.56 (2 H, t, J=6.3 Hz), 3.36 (3 H,s), 3.02-2.88 (2 H, m), 2.66 (1 H, dd, J=5.4, 13.7 Hz), 2.49 (1 H, dd,J=9.0, 13.7 Hz), 2.34 (3 H, s), 2.12-2.03 (2 H, m), 1.92-1.51 (8 H, m),1.14 (3 H, d, J=6.3 Hz), 1.06 (3 H, d, J=5.6 Hz), 0.96 (3 H, d, J=6.3Hz), 0.91 (6 H, d, J=7.0 Hz).

EXAMPLE C2 Preparation of Compound C1

[0083] Example C1 is repeated with 8 mmol cerium trichloride. The yieldis similar to that in example C1. However, the ratio of 5(S)- to5(R)-stereoisomer is 75:25.

[0084] D) Preparation of

EXAMPLE D1

[0085] The removal of the pseudoephedrine group and the reductiveremoval of the hydroxyl group are carried out at the same time. To asolution of 0.0029 9 (0.14 mmol) copper(acetate)₂xH₂O in 0.4 ml aceticacid, 0.00474 g (0.725 mmol) zinc powder is added and the mixturestirred for 15 minutes at ambient temperature. A solution of 0.1 g(0.145 mmol) of the 5S-diastereomer of compound C1 in 0.8 ml aceticacid/water (3:1) is then added and stirred for 55 hours at ambienttemperature. The mixture is filtered via Celite and then washed with alittle water/ethyl acetate. The filtrate is extracted with 4×10 ml ethylacetate and the combined organic phases then washed with water. Theorganic phase is separated off and dried with anhydrous sodium sulfate.After the solvent has been evaporated off, the residue is purified byflash chromatography (mobile phase cyclohexane/ethyl acetate 3:1).Compound D1 is obtained in a yield of 41% as a clear colourless liquid.

[0086] Characterization: [α]_(D) ²⁰=+6.3 (c=1.0, CHCl₃). ¹H-NMR (300MHz, CDCl₃): δ 7.36-7.20 (5 H, m), 6.75 (1 H, d, J=8.1 Hz), 6.68 (1 H,d, J=1.9 Hz), 6.66 (1 H, dd, J=1.9, 8.1 Hz), 4.35 (1 H, ddd, J=4.1, 5.1,8.5 Hz), 4.11 (1 H, dt, J=6.6, 12.7 Hz), 4.05 (1 H, dt, J=6.3, 12.7 Hz),3.83 (3 H, s), 3.69 (1 H, d, J=13.2 Hz), 3.64 (1 H, d, J=13.2 Hz), 3.58(2 H, t, J=6.1 Hz), 3.37 (3 H, s), 2.82 (1 H, ddd, J=4.1, 4.6, 8.5 Hz),2.66 (1 H, dd, J=4.9, 10.5 Hz), 2.63 (1 H, dd, J=5.1, 10.5 Hz),2.22-2.06 (5 H, m), 1.93 (1 H, ddd, J=6.8, 8.5, 13.4 Hz), 1.72 (1 H, m),1.51 (1 H, m), 1.33 (1 H, ddd, J=4.6, 7.6, 13.4 Hz), 1.28 (1 H, bs),1.15 (1 H, ddd, J=4.4, 8.5, 13.4 Hz), 1.02 (3 H, d, J=6.8 Hz), 0.94 (3H, d, J=6.8 Hz), 0.93 (3 H, d, J=6.8 Hz), 0.86 (3 H, d, J=6.8 Hz).¹³C-NMR (75 MHz, CDCl₃): δ 179.35 (C═O), 148.58 (aromatic), 147.93(aromatic), 140.68 (aromatic), 134.10 (aromatic), 128.63 (2 C,aromatic), 128.53 (2 C, aromatic), 127.28 (aromatic), 121.44 (aromatic),114.63 (aromatic), 112.08 (aromatic), 82.02 (OCH), 69.62 (OCH₂), 66.36(OCH₂), 58.91 (NCH), 57.65 (OCH₃), 56.26 (OCH₃), 53.43 (NCH₂), 46.20(CH), 43.12 (CH), 36.68 (CH₂), 32.22 (CH₂), 29.89 (CH₂), 29.43 (CH),29.39 (CH), 24.52 (CH₂), 20.68 (CH₃),19.78 (CH₃),18.60 (CH₃),18.19(CH₃).

[0087] E) Preparation of

EXAMPLE E1

[0088] A mixture of 0.591 g D1, 0.418 g3-amino-2,2-dimethylpropionamide, and 0.023 g 2-hydroxypyridine in 5.9ml triethylamine is stirred over a period of 16 hours at 90° C. Then 3.3ml triethylamine is distilled off over a period of 0.5 hours, and theresidue is agitated for a further 8.5 hours at 90° C. The cooledreaction mixture is extracted between ethyl acetate (3×500 ml),saturated aqueous sodium hydrogencarbonate solution (1×500 ml) andsaturated sodium chloride solution (1×500 ml). The combined organicphases are dried over 4 g sodium sulfate, filtered and concentrated on arotary evaporator. The residue is dried, and crude title compound E1 isobtained as an oil.

[0089] Characterization: ¹H-NMR (300 MHz, CDCl₃): δ 7.37-7.20 (5 H, m),6.76 (1 H, d, 8.1 Hz), 6.70 (1 H, d, J=1.9 Hz), 6.67 (1 H, dd, J=1.9,8.1 Hz), 6.41 (1 H, dd, J=6.0, 6.4 Hz), 6.35 (1 H, bs), 5.52 (1 H, bs),4.10 (1 H, dt, J=6.2, 12.0 Hz), 4.06 (1 H, dt, J=6.2, 12.0 Hz), 3.82 (3H, s), 3.64 (2 H, s), 3.61 (1 H, m), 3.58 (2 H, t, J=6.2 Hz), 3.44 (1 H,dd, J=6.4, 13.0 Hz), 3.39 (1 H, dd, J=6.4, 13.0 Hz), 3.36 (3 H, s), 2.59(1 H, dd, J=4.4, 13.0 Hz), 2.53 (1 H, dt, J=4.0, 7.6 Hz), 2.18 (1 H, dd,J=8.4, 13.0 Hz), 2.10 (2 H, m), 1.92-1.23 (8 H, m), 1.17 (2 H, s), 0.96(3 H, d, J=6.8 Hz), 0.93 (3 H, d, J=6.8 Hz), 0.91 (3 H, d, J=6.8 Hz),0.85 (3 H, d, J=6.8 Hz).

[0090] F) Preparation of

EXAMPLE F1

[0091] A suspension of 0.12 g 10% Pd/C, 0.119 g (0.185 mmol) compound E1and 0.185 mmol ethanolamine in 3 ml methanol is added to a pressurizedvessel, 1 atmosphere of hydrogen pressure, is applied and the suspensionthen stirred for 3 hours at ambient temperature. Filtration is thencarried out and the solvent evaporated off. Compound F1 is obtained in ayield of 87% as a colourless oil.

[0092] Characterization: ¹H-NMR (300 MHz, CDCl₃): δ 6.82 (1 H, d, J=8.1Hz), 6.70 (1 H, d, J=1.9 Hz), 6.68 (1 H, dd, J=1.9, 8.1 Hz), 6.32 (1 H,dd, J=6.0, 6.4 Hz), 5.40 (1 H, bs), 4.97 (1 H, d, J=9.0 Hz), 4.65 (1 H,dd, J=4.8, 8.3 Hz), 4.12 (2 H, t, J=6.2 Hz), 4.00 (1 H, m), 3.86 (3 H,s), 3.58 (2 H, t, J=6.2 Hz), 3.56 (1 H, dd, J=6.0, 13.8 Hz), 3.36 (3 H,s), 3.23 (1 H, dd, J=6.4, 13.8 Hz), 2.68 (1 h, dd, J=3.5, 13.6 Hz), 2.40(2 H, t, 6.2 Hz), 2.20-1.42 (9 H, m), 2.05 (3 H, s), 1.82 (3 H, s), 1.23(6 H, s), 0.99 (3 H, d, J=6.8 Hz), 0.91 (6 H, d, J=6.8 Hz), 0.88 (3 H,d, J=6.8 Hz). MALDI-TOF MS: 659.0 (M+Na), 674.9 (M+K).

What is claimed is:
 1. A process for the preparation of compounds offormula I and their physiologically acceptable salts,

wherein R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₅ isC₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆-alkyl,C₁-C₆alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl,C₁-C₆alkylamino-C₁-C₆-alkyl, C₁-C₆-dialkylamino-C₁-C₆-alkyl,C₁-C₆-alkanoylamido-C₁-C₆-alkyl, HO(O)C—C₁-C₆-alkyl,C₁-C₆alkyl-O—(O)C—C₁-C₆alkyl, H₂N—C(O)—C₁-C₆alkyl,C₁-C₆alkyl-HN—C(O)—C₁-C₆alkyl or (C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl,comprising the steps a) reaction of a compound of formula II,

wherein R₄ is as defined above, with a hydroxylamine of formula ZNHOH(III), wherein Z is a removable protecting group, to form a compound offormula IV,

b) reaction of a compound of formula IV with a metal organic derivativeof a compound of formula V,

wherein R₁, R₂ and R₃ are as defined above and Y is Cl, Br or I, to forma compound of formula VI,

c) removal of the hydroxyl group to form a compound of formula VII,

d) removal of the pseudoephedrine protecting group to form compounds offormula VIII,

or performance of step d) before step c), or of steps c) and d) togetherin one reaction vessel, e) reaction of a compound of formula VIII withan amine of formula R₅—NH₂ to form a compound of formula IX

and f) removal of protecting group Z for the preparation of compounds offormula I.
 2. A process according to claim 1, comprising preparation ofthe 5(S)-diastereomer of formula Ia


3. A process according to claim 1 comprising an embodiment wherein R₁ isC₁-C₄alkoxy or C₁-C₄alkoxy-C₁-C₄alkyloxy, R₂ is C₁-C₄alkoxy, R₃ isC₁-C₄alkyl, R₄ is C₁-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl which ifnecessary is N-monosubstituted or N-di-C₁-C₄alkyl-substituted.
 4. Aprocess according to claim 3 comprising an embodiment wherein R₁ ismethoxy-C₂-C₄alkyloxy, R₂ is methoxy or ethoxy, R₃ is C₂-C₄alkyl, R₄ isC₂-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl.
 5. A process according to claim4 comprising an embodiment wherein R₁ is 3-methoxy-prop-3-yloxy, R₂ ismethoxy, R₃ and R₄ are 1-methyleth-1-yl, and R₅ isH₂NC(O)—[C(CH₃)₂]—CH₂—.
 6. A process according to claim 1, comprising anembodiment wherein Z in formula III is benzyl.
 7. A process according toclaim 1, comprising the reaction of a compound of formula II immediatelyafter preparation with a hydroxylamine.
 8. A process according to claim1, comprising a reaction temperature in process step a) of −20 to 50° C.9. A process according to claim 1, comprising an embodiment wherein themetal organic derivatives in process step b) are those of formula X,

wherein Y₁ is an alkali metal or —MeY, wherein Y is Cl, Br or iodine andMe is Mg, Zn, Hg or Cd.
 10. A process according to claim 1, comprising areaction temperature in process step b) of −70 to 100° C.
 11. A processaccording to claim 1, comprising the reaction in process step b) beingcarried out in the presence of a heavy metal salt, in particular ceriumslats.
 12. A process according to claim 1, comprising the removal of thehydroxyl group in process step c) being carried out in an aqueous acidicmedium with nascent hydrogen.
 13. A process according to claim 1,comprising the removal of the pseudoephidrine group in process step d)being carried out in an aqueous acidic medium.
 14. A process accordingto claim 1, comprising process steps c) and d) being carried out at thesame time in one reaction vessel.
 15. A process according to claim 1,comprising the reaction in process step e) being carried out in thepresence of alcohols or amines, which form activated carbonic esters orcarboxamides with the carboxylic acids of formula VIII.
 16. A processaccording to claim 1, comprising a reaction temperature in process stepe) of 40 to 150° C.
 17. A process according to claim 1, comprising theremoval of the protecting group Z in process step f) being carried outcatalytically by hydrogenation in the presence of homogeneous orheterogeneous precious metal catalysts or Raney-Nickel.
 18. A processaccording to claim 1, comprising a reaction temperature in process stepf) of 0 to 200° C.
 19. Compounds of formula IV,

wherein R₄ and Z are as defined in claim
 1. 20. Compounds of formula XIin the form of 5(S)- or 5(R)-diastereomers or mixtures thereof,

wherein R₁, R₂, R₃, R₄ and Z are as defined in claim 1 and X₂ is H orOH.
 21. Compounds of formula XII in the form of 5(S)- or5(R)-diastereomers or mixtures thereof,

wherein R₁, R₂, R₃, R₄ and Z are as defined in claim 1 and X₂ is H orOH.
 22. Compounds of formula XIII in the form of 5(S)- or5(R)-diastereomers or mixtures thereof,

wherein R₁, R₂, R₃, R₄, R₅ and Z are as defined in claim 1.